Autophagy is an evolutionarily conserved lysosomal degradation pathway to essentially self-digest some cellular components (see, Levine and Kroemer (2008) CELL, 132, p. 27-42). This self-digestion process helps cells remove extraneous or damaged organelles, defective or mis-folded proteins, and even invading microorganisms. It has been speculated that autophagy is down-regulated in a number of diseases, for example, cystic fibrosis (Luciani et al. (2011) AUTOPHAGY, 7, p. 104-106).
Cystic fibrosis (CF) has been described as one of the most common, life-shortening autosomal recessive hereditary diseases in the Caucasian population. It is an orphan disease that affects approximately 30,000 children and adults in the U.S. (70,000 worldwide); and about 1,000 new cases are diagnosed each year. The disease is characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which results in either loss or impaired ability to transport chloride ions by various secretory and absorptive epithelial cells in the lung, pancreas, liver, and intestine (see, for example, Derichs (2013) EUR. RESP. REV, 22, p. 58-65). The resulting decrease in anion transport and imbalance in fluid homeostasis produce thick and viscous mucus in the lungs, which can obstruct airways, causing chronic inflammation and infection. This leads to a progressive decline in lung function and a limited life expectancy in patients with the more severe form of the disease.
The CFTR is a cAMP-activated ATP-gated ion channel composed of approximately 1,480 amino acids. The protein consists of 5 domains: two transmembrane domains, each containing 6 spans of alpha helices. Each transmembrane domain is connected to a nucleotide binding domain (NBD). The first NBD is connected to the second transmembrane domain by a regulatory “R” domain. The gene encoding CFTR was reported in year 1989 (see, Rommens et al. (1989) SCIENCE, 245, p. 1059-1065). Since then, over 1900 sequence variations in the CFTR gene have been identified, the majority of which fall into one of the following 6 classes: Class I mutations result from non-sense and frame shift mutations, which reduce the quantity of the CFTR; Class II mutations have folding defects which result in premature degradation; Class III mutations result in limited channel gating; Class IV mutations have conductance defects; Class V mutations have a transcriptional defect that results in a reduced quantity of the CFTR being produced; Class VI mutations have a high turnover of the CFTR at the channel surface (see, for example, Rowntree and Harris (2003) ANN. HUM. GENET., 67, p. 471-485; Zielenski (2000) RESPIRATION, 67, p. 117-133; and MacDonald et al. (2007) PAEDIATRIC DRUGS, 9, p. 1-10).
To manifest the debilitating CF disease, an individual inherits two defective CFTR alleles, one from each parent. Of the over 1900 sequence variations in the CFTR that have been identified, the following 4 mutations have a worldwide prevalence of around 1-3% each: G551D, W1282X, G542X and N1303K. The most prevalent CFTR mutation, with an allelic frequency of about 90% worldwide, is the ΔF508 mutation (a Class II mutation, deletion of a phenylalanine which causes protein mis-folding and premature degradation). The ΔF508 deletion mutation can be manifested in either homozygous or heterozygous form.
Research on therapeutic interventions has identified several anti-inflammatory and anti-infective therapies useful in controlling certain debilitating symptoms of CF (see, for example, Nichols et al. (2008) CLINIC REV. ALLERG. IMMUNOL., 35, p. 135-153). More recently, disease-modifying therapies have been introduced to address the defective CFTR. CFTR “potentiators” were designed to increase the open probability of CFTR channels that are available at the membrane but have gating (Class III) and conductance (Class IV) mutations. Ivacaftor (VX-770) is a CFTR potentiator that received FDA approval for the treatment of CF patients with gating mutations that included G551D, G178R, S549N, S549R, G551S, G124E, S1251N, S1255P, and G1349D (see, for example, Van Goor et al. (2009) PNAS, 106, p. 18825-18830). However, patients with these gating mutations represent only a small percentage of CF patients worldwide.
In addition to CFTR potentiators, clinical developments have been reported evaluating the potential of a CFTR “corrector” to increase the amount of CFTR that can be delivered to the cell membrane. VX-809 (Lumacaftor) is a CFTR corrector that has recently been approved by the FDA, when used in combination with Ivacaftor, in CF patients with homozygous ΔF508 mutation (see, for example, Van Goor et al. (2011) PNAS, 108, p. 18843-18848; and Ren et al. (2013) MOL. BIOL. CELL, 24, p. 3016-3024).
Despite the efforts made to date, there is still an ongoing need for additional compositions and methods for treating disorders associated with dysregulation of autophagy, for example, CF, and in particular certain forms of CF associated with mutations that are difficult to treat using existing therapies.